The Mitochondrial Life Cycle Determines beta-Cell Maturity through Activation of the Integrated Stress Response

Mitochondrial function is pivotal to β-cell competence. The mitochondrial life cycle balances mitochondrial biogenesis and turnover (mitophagy) to ensure optimal metabolic function. Human type 2 diabetic (T2D) β-cells are known to develop mitochondrial structural/functional defects, suggestive of a defective mitochondrial life cycle. However, it is unclear if these defects are a cause or consequence of T2D. Here, we observed that human T2D β-cells had reduced mitophagic flux, mtDNA content, and expression of mitochondrially encoded genes. To test the importance of the mitochondrial life cycle to drive β-cell failure in T2D, we developed 2 distinct β-cell specific mouse models: βTfamKO (to deplete mtDNA) and βClec16aΚΟ (to impair mitophagy). We observed age dependent loss of glucose tolerance, glucose stimulated insulin secretion and β-cell mass in both models, which was exacerbated by obesity in βClec16aΚΟ mice. Loss of β-cell mass was largely independent of changes in proliferation or apoptosis but rather, due to an induction of β-cell immaturity. Using lineage tracing approaches, we confirmed that βClec16aKO and βTfamKO mice induce formation of both insulin-negative immature β-cells and β-to-α cell transdifferentiation. Further, high-throughput gene expression profiling, biochemical, and metabolic assays highlighted that either Clec16a or Tfam deficiency induces an aberrant retrograde signaling program, manifested by reductions in cellular ATP and activation of the integrated stress response (ISR). Importantly, inhibition of the ISR in vivo ameliorated glucose intolerance, defective insulin secretion, β-cell immaturity, and loss of β-cell mass, suggesting that aberrant retrograde signaling may directly lead to loss of β-cell identity. Taken together, our studies illustrate that a unified mitochondrial lifecycle is necessary to maintain β-cell mass and identity and may be targeted to prevent β-cell failure in T2D. Disclosure G. Pearson: None. N. Lawlor: None. J. Zhu: None. E. M. Walker: None. E. C. Reck: None. M. L. Stitzel: None. S. Soleimanpour: None. Funding American Diabetes Association (1-19-PDF-063 to G.P.)